In the treatment of diabetes mellitus, many varieties of insulin preparations have been suggested and used, such as regular insulin, Semilente® insulin, isophane insulin, insulin zinc suspensions, protamine zinc insulin, and Ultralente® insulin. As diabetic patients are treated with insulin for several decades, there is a major need for safe and life quality improving insulin preparations. Some of the commercial available insulin preparations are characterized by a fast onset of action and other preparations have a relatively slow onset but show a more or less prolonged action. Fast acting insulin preparations are usually solutions of insulin, while retarded acting insulin preparations can be suspensions containing insulin in crystalline and/or amorphous form precipitated by addition of zinc salts alone or by addition of protamine or by a combination of both.
In addition, some patients are using preparations having both a fast onset of action and a more prolonged action. Such a preparation may be an insulin solution wherein protamine insulin crystals are suspended. The invention relates to such a suspension in a premixed form.
Acta Pharmaceutica Nordica 4(4), 1992, pp. 149-158 discloses insulin preparations in which the NaCl concentration has been varied in the range of 0 to 250 mM. The major part of the preparations, including all preparations which additionally comprise glycerol, contains a rather high amount of NaCl, i.e. 0.7% corresponding approximately to a concentration of 120 mM. It is stated in this document that whereas NaCl has a stabilizing effect on insulin preparations, glycerol and glucose leads to increased chemical deterioration.
U.S. Pat. No. 5,866,538 discloses insulin preparations with glycerol and/or mannitol and low NaCl concentrations. This reference does not describe suspensions or the presence of protamine.
U.S. Pat. No. 6,127,334 discloses suspensions of insulin AspB28 containing hydrochloric acid, ZnCl2 solution, protamine sulphate solution, m-cresol, phenol, glycerol, disodium monohydrogenphosphate and water. Other examples include the ingredients above including mannitol and/or NaCl and/or LYSB28-ProB29-insulin. The examples thus differs in as well ingredients as methods of preparing the formulation. The preparations solve the problem of providing suspensions which are resistant to physical stress.
U.S. Pat. No. 5,547,930 describes solutions of AspB28 insulin containing hydrochloric acid, ZnCl2 solution, protamine sulphate solution, m-cresol, phenol, glycerol, di-sodium monohydrogenphosphate and water. The examples thus differs in as well ingredients as methods of preparing.
The invention thus provides a novel formulation for insulin suspensions, and a novel method of preparing the formulation.